Summary Porphyromonas gingivalis, a keystone pathogen in chronic periodontitis secretes a large variety of virulence factors, including an enzyme, peptidylarginine deiminase (PAD), unique for pathogenic species of the Porphyromonas genus. Alike human endogenous PADs, the bacterial enzyme converts arginine residues in proteins to citrulline but it has a strong preference for C-terminal Arg. We postulated that P. gingivalis PAD (PPAD) activity not only contributes to pathogenesis of periodontitis but also it may be involved in the breakdown of immunotolerance and the development of rheumatoid arthritis (RA), a diseases driven by autoantibodies targeting citrullinated epitopes. This contention is supported by findings that PPAD, in conjunction with Arg-specific gingipain proteases (Rgps), can generate a large spectrum of citrullinated peptides derived from bacterial and host proteins, including fibrinogen and enolase ? both accepted autoantigens in RA. Also, citrullinated proteins of P. gingivalis stimulate human gingival fibroblasts (HGF) to produce prostaglandin E2 (PGE2), one of the most potent mediators of bone resorption implicated in the pathogenesis of PD and RA. Moreover, our unpublished data show that both resting and P. gingivalis citrullinome-stimulated HGFs, derived from periodontitis patients, produce significantly more PGE2 than cells from healthy donors. Finally, we discovered two allelic forms of the ppad gene among P. gingivalis clinical isolates, one encoding a superactive isoform of the enzyme, which crystal structure suggests that it binds substrates with higher affinity than the other form of PPAD. The tighter substrate binding may contribute to proposed second important function of PPAD as the carrier protein of haptens (bacteria and/or host protein- derived citrullinated peptides) presented to B cell, followed by T cell activation and the breakdown of immunotolerance in a hapten/carrier mechanism. Based on these findings we postulate that PPAD is directly responsible for the breakdown of immunotolerance and subsequent anti-citrullinated protein antibody (ACPA) production - key pathological events preceding clinical onset of RA; and the severity of PD and its link to RA is associated with the occurrence of a superactive variant of PPAD expressed by subset of P. gingivalis strains. To experimentally verify these hypotheses, we propose the following specific aims: (i) investigate the functional relevance of citrullinated bacterial proteins in pathological interactions between P. gingivalis and fibroblasts; (ii) determine if PPAD targeting by T cells provides help for the production of ACPA through a hapten/carrier mechanism; and (iii) analyse the prevalence of P. gingivalis strains carrying the superactive PPAD gene in the context of the severity of PD and relation to associated RA. Successful completion of this project will drive the field forward by providing a novel perspective to the understanding the pathogenesis of PD-RA associations, thus offering venues to develop novel strategies to treat these debilitating diseases.